An Astrocyte-Targeted Nanoplatform with Ultrasound-Responsive Fluorescence Switch for Synergistic Chemo-Sonothermal Therapy of Cognitive Impairment

The escalating global burden of cognitive impairment, driven significantly by environmental neurotoxins such as volatile organic compounds (VOCs), presents a critical public health crisis. Therapeutic intervention remains largely stagnant, primarily due to the formidable blood-brain barrier (BBB) and the lack of precise, target-specific delivery systems capable of real-time monitoring. Herein, we report a pioneering astrocyte-targeted nanoplatform (UAFNPs) that uniquely integrates an ultrasound-responsive fluorescent switch with synergistic chemo-sonothermal therapy for VOC-induced cognitive disorders. Capitalizing on the intrinsic plasmonic properties of gold nanotriangles, UAFNPs features an innovative "off-on" mechanism: the system remains optically silent during systemic circulation due to efficient fluorescence quenching, yet generates a bright, localized signal upon ultrasound exposure, enabling on-demand activation, minimal-background monitoring during circulation of brain accumulation. Critically, this platform efficiently traverses the BBB and selectively homes to reactive astrocytes. Upon focused ultrasound irradiation, UAFNPs generates mild therapeutic hyperthermia and triggers the controlled release of a potent neuroprotective payload. In a 1-bromopropane-induced cognitive impairment model, this combinatorial strategy potently reversed cognitive deficits by reprogramming astrocyte polarization from the neurotoxic A1 to the neuroprotective A2 phenotype via suppression of the TRAF6-TAK1-NF-κB axis. This work establishes a paradigm-shifting blueprint for precision neurotheranostics, offering unprecedented spatiotemporal control and significant translational potential for treating complex neurological disorders.